by Catherine Goh

Month: October 2015

Previous rumours were finally confirmed when Biogen announced this week that they are cutting back 11% of their workforce by the end of 2015. Several projects in their pipeline will also be shut down which include Phase III development of oral drug Tecfidera for its use in secondary progressive multiple sclerosis, Phase II development of anti-TWEAK in lupus nephritis and other preclinical projects in immunology and fibrosis research. These restructuring reforms are projected to save $250 million in yearly operating expenses though may incur about $90 million to implement.

The resulting savings from the cutbacks are to be channeled toward the development of anti-Alzheimer’s disease drugs. One of these is aducanumab, a Phase III beta-amyloid antibody that sent the public in a hopeful frenzy as a Phase I clinical trial revealed dose-dependent cognitive improvement when the drug was given at 3 mg/kg and 10 mg/kg doses. A repeat of the trial at a 6 mg/kg dose however failed to reproduce this cognitive improvement although it did reduce beta amyloid levels to a significant extent. MMSE (mini mental state examination) scores for placebo group worsened by 2.81 points on average at 52 weeks compared to 2.18 points in the 1 mg/kg, 0.70 in the 3 mg/kg, 1.96 in the 6 mg/kg and 0.56 in the 10 mg/kg. These confounding results exemplify the challenges faced with developing drugs for this complex disease. As a sidenote:For a more personal insight into this debilitating disease, watch Still Alice, where Julianne Moore gave an Academy Award winning performance, depicting a linguistics professor suffering from early-onset AD.

Despite this, Biogen is pressing on, recruiting 1350 patients for the Phase III trial of aducanumab that would extend over 5 years. It is also focussed on development of BAN2401, a Phase II antibody with the same target, and E2609, a BACE inhibitor. Consistent with their focus on neurological disease, Biogen has also been forming strategic partnerships with research institutes such as the Parkinson’s Institute and Clinical Center and Columbia University Medical Centre to further understanding on Parkinson’s disease and Amyotrophic Lateral Sclerosis respectively.

Aside from neurology, Biogen is invested in developing drugs towards hemophilia as well as autoimmune diseases such as multiple sclerosis and inflammatory bowel disease.

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I have been reading a book called “The Innovators” by Walter Isaacson which details the history of the computer and how we got to the present state of computing technology. A brilliant read for anyone interested to have an insight on the people, the environment, and the thinking during the time of each invention. Isaacson’s accounts start from the 18th century with Ada Lovelace’s (featured in the image above) first thoughts on creation of a computer that can fulfill multiple functions from math to music, to the 1980s where Gordon Moore and Robert Noyce were making the first microchips from their startup – Intel, closely followed by the invention of the first personal computer (the Altair) by Ed Roberts. We learn more about how Bill Gates was an annoying skinny geek with an extreme ability to focus and sharp business instincts passed down from his wealthy parents, to the actual impact Al Gore made in starting the Internet, up to present day when Larry Page and Sergey Brin created Google.

Noteworthy is what brought about all these particular inventions. People tend to have a romantic notion that innovation tends to come from lone geniuses working in their garages. Isaacson however, notes that significant advances were usually made by groups of people and often in an environment with enough resources to see the invention through. Although a man called Atanasoff was one of the first to build a partly electronic computer in his basement in Iowa, it was John Mauchly along with Presper Eckert who got recognition for building ENIAC (first computer) at the University of Pennsylvania. While the former’s invention languished in a basement and was eventually dismantled and forgotten, the latter was built by a team of engineers and well-funded by the government. Mauchly also got his ideas not by himself, but rather from talking to numerous sources, including Atanasoff himself, before he could combine the various ideas into a unique model which he then strove to implement.

The concept of tinkering and building something was also well-ingrained in many inventors. During the 1970s, there were not quite as many distractions as there are today, and many people became hobbyists, cultivating communities that take a do-it-yourself approach. As such people like Gordon Moore, Paul Allen (who started Microsoft with Bill Gates) and Steve Wozniak often started assembling their own radios and computers or experimenting with chemistry sets from a young age. Many of the kids today do not even know what lies inside a computer, much less try to assemble one. Understanding the basics are often a requirement before attempting to break new frontiers.

Another trait many inventors tended to have was an opposition to authority. Bill Gates and Steve Jobs are probably most well-known for dropping out of college to start their own companies. The fact that the Internet is not localized to a specific hub but is spread across decentralized units was also the result of people fighting to prevent control by any one entity. Even Larry Page and Sergey Brin concluded that their Montessori schooling, where people do not tell you what to do but you create your own path, was a key contributor to their current success. I often worry that Singaporeans bend too easily to authority. The freedom of the individual, so aggressively defended in America, likely contributes to their intense self- belief that one can do anything, even against large scary bureaucracies. Without this belief, people would not even attempt to go against the grain and invent something new.

So you want to invent something? Be it in computing or biology, talk to smart people, be a team-player, experiment and don’t believe anyone who tells you its impossible!

Devised by the Dr Chad Mirkin’s group in Northwestern University in 1996, SNAs are composed of about a hundred strands of nucleic acids conjugated at their ends to a spherical nanoparticle core, usually made of gold, but in some instances can even be hollow. The key thing about SNAs is the ability for them to be taken up effectively by the cell without the need of cumbersome and sometimes toxic transfecting reagents. The particle is taken up by cell surface receptors into endosomes that prevent their contact with nucleases which normally degrade unprotected nucleic acid strands. Already several proof-in-concept studies have been done demonstrating their enhanced uptake. SNAs applied to the skin of mice were able to penetrate into skin cells to knockdown genes involved in psoriasis. They were also able to cross the blood-brain-barrier when injected into tail veins of mice, knocking down potential oncogenes and extending lifespan in a glioblastoma mouse model.

Mirkin is a renowned chemist specializing in nanotechnology and has founded several companies using SNAs. Nanosphere in Northbrook, Illinois, uses SNA’s additional ability to bind nucleic acids at low concentrations to detect the presence of microbes or pathogens in tissue samples. Aurasense Technologies now named Exicure, have attracted more than $27 million in funding and are using SNAs to stimulate an immonomodulatory response against cancer cells. The SNAs have sequences that resemble Toll-like receptor agonists and when administered in SNA form were noted to bring about an enhanced immunostimulatory response as compared to linear forms. They have already released positive preclinical data published in PNAS and their use in combination with checkpoint inhibitors are currently being explored in cancer treatment.

Northwestern University has recently received a $11.7 million grant from the US National Cancer Institute to apply this technology in the field of gene therapy and applications for this are proving to be wide-ranging. This has the potential to change how RNAi therapies are currently being administered, but it remains to be seen how well existing RNAi companies will take to this patented technology.

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It is Oktoberfest season here in Munich and beer consumption is at its highest. Beer is one of the world’s oldest beverages, with evidence of its existence dating back to 5000 BC in ancient Egypt and Mesopotamia. It is made by the fermentation of sugars usually derived from malted barley to produce ethanol and carbon dioxide. Hops are often added to increase bitterness and they contribute to that thick foamy head we see on the surface of beers. Various strains of yeast carry out the fermentation process and these differ in terms of their growth rate and resultant ester production. Esters are what contributes to the assortment of fragrances associated with beer.

Brewing beer is indeed a science. There are an array of parameters that affect the brewing process and resultant flavour of the beer. These include minerals in the water, the temperature of fermentation, the strain of yeast used, the amount of aeration and the length of fermentation. To gain an insight on the level of science involved, check out Chad Yacobson’s blog. He did a Masters degree in brewing and distilling in Edinburgh and recorded his laboratory findings in an open-source fashion, mainly a wordpress blog. It features an array of agar plates with a dizzying variety of cultivated yeast colonies of differing shapes and colours. He also had to smell each plate, and the esters the yeast produces can give rise to scents like “Hawaiian punch” and “cocoa buttery” aromas. Not too bad a scientific project! He focused in particular on a wild yeast strain called Brettanomyces spp. and now has started his own business in Colorado selling Brettanomyces-fermented beers.

It is interesting however that with the current ease in genetic manipulation, especially of simple organisms like yeast, that not a single beer on the market is made using genetically-modified yeast. This is mainly due to the negative impression people have on genetically-modified foods. This may change in the near future though as the US FDA have established some headway into getting these genetically-modified yeasts into the market. Already, some wines are being produced using a genetically-modified strain of yeast called ML101 which is deficient in a gene that produces a headache-inducing chemical.

In parallel with brewing beer, scientists have recently found a way to induce yeast to ferment sugars into opiates. John Dueber’s group at the University of California, Berkeley, and the lab of Vincent Martin of Concordia University in Montreal, Canada, have revealed all steps aside from one of an engineered yeast pathway that converts glucose to morphine. Morphine is currently produced from poppy, and this advance would make it much easier and cheaper to produce the analgesic. But of course this generates the obvious risk of home beer-brewers making their own pain-numbing concoctions. Not to mention the wide network of illicit drug dealers that would not hesitate to delve into the science of yeast fermentation to produce opiates for the current market – 16 million people take opiates illegally.

With synthetic biology on the rise, it is indeed necessary to enforce strict regulations on its applications. When it comes to brewing better beer however, I say bring on those GM yeast!